rs794728922

Variant names:

• chr3-38560249-CTTG-C
• rs794728922
• NM_001099404.2:c.4140_4142delCAA

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM4_Supporting PP5

The NM_000335.5(SCN5A):​c.4137_4139delCAA​(p.Asn1379del) variant causes a disruptive inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SCN5A NM_000335.5 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4 U:1 O:1
• Conservation: PhyloP100: 4.20

Genes affected

SCN5A (HGNC:10593): (sodium voltage-gated channel alpha subunit 5) The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a topological_domain Extracellular (size 51) in uniprot entity SCN5A_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000335.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000335.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 3-38560249-CTTG-C is Pathogenic according to our data. Variant chr3-38560249-CTTG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 201570.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=4, Uncertain_significance=1, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SCN5A	NM_001099404.2	c.4140_4142delCAA	p.Asn1380del	disruptive_inframe_deletion	Exon 23 of 28	ENST00000413689.6	NP_001092874.1
SCN5A	NM_000335.5	c.4137_4139delCAA	p.Asn1379del	disruptive_inframe_deletion	Exon 23 of 28	ENST00000423572.7	NP_000326.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SCN5A	ENST00000413689.6	c.4140_4142delCAA	p.Asn1380del	disruptive_inframe_deletion	Exon 23 of 28	5	NM_001099404.2	ENSP00000410257.1
SCN5A	ENST00000423572.7	c.4137_4139delCAA	p.Asn1379del	disruptive_inframe_deletion	Exon 23 of 28	1	NM_000335.5	ENSP00000398266.2

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Brugada syndrome 1 Pathogenic:2

Jan 31, 2017

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2024

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS) (MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS) (MIM#603830). Dilated cardiomyopathy 1E (DCM) (MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0213 - In-frame deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated DIII-S5-S6 pore region (PMID: 25348405). (I) 0705 - No comparable inframe deletion variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been reported in multiple individuals with Brugada syndrome (ClinVar, PMID: 28159958, 28341781, 31516285, 32893267). It has also been reported as VUS once in ClinVar and in an individual with a family history of unexplained cardiac arrest (PMID: 29759671;). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Functional data using patch clamp assay has shown this variant results no detectable sodium current (PMID: 28159958). However, patch clamp assays have been shown to be unreliable, therefore results from these studies are used with caution during variant classification. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided Pathogenic:1 Other:1

Oct 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.4140_4142del, results in the deletion of 1 amino acid(s) of the SCN5A protein (p.Asn1380del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with autosomal dominant Brugada syndrome (PMID: 28159958, 28341781, 28600387, 29759671, 31737537; external communication). ClinVar contains an entry for this variant (Variation ID: 201570). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects SCN5A function (PMID: 28159958). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

-

GeneDx

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

The c.4140_4142delCAA in-frame deletion results in the removal of a highly conserved Asparagine amino acid at position 1380 in the SCN5A gene. Missense variants in this same residue (N1380K) and in nearby residues (V1378M, S1382I) have been reported in association with Brugada syndrome, supporting the functional importance of this residue and this region of the protein. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Cardiovascular phenotype Pathogenic:1

Dec 14, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4140_4142delCAA variant (also known as p.N1380del) is located in coding exon 22 of the SCN5A gene. This variant results from a deletion of nucleotides CAA at position 4140 to 4142. This results in the in-frame deletion of an asparagine residue at codon 1380. This alteration has been reported in several relatives with varying degrees of cardiac conduction disorder and a family history of sudden death in one family (Yang Z et al. Acta Biochim. Biophys. Sin. (Shanghai). 2017;49(3):270-276). This variant has also been detected in two cardiac arrest survivors (Mellor G et al. Circ Cardiovasc Genet. 2017;10:e001686; Tadros R et al. J Am Coll Cardiol EP. 2017;in press). Functional studies indicate that this alteration causes a dominant negative loss of SCN5A function in mammalian kidney cells (Yang Z et al. Acta Biochim. Biophys. Sin. (Shanghai). 2017;49(3):270-276). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012;7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not specified Uncertain:1

Jul 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SCN5A c.4140_4142delCAA (p.Asn1380del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant was absent in 250510 control chromosomes. c.4140_4142delCAA has been reported in the literature in a proband with recurrent syncope and a paternal family history of sudden unexpected nocturnal death from a family that also reported sub-clinical or asymptomatic carriers (Yang_2017). A Flecainide challenge test to confirm Brugada diagnosis was not performed in this study. It has subsequently been reported in an individual from a clinically characterized cohort with Brugada syndrome (Yamagata_2017), as a VUS in an individual from a cohort with Ajmaline positive unexplained cardiac arrest (UCA) or sudden unexplained death (SUD) (Tadros_2017), as a VUS in the CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) study (Mellor_2017) and as a VUS in a pediatric cohort with cardiac conduction disorders (Baruteau_2018). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a loss of channel function as measured by no detectable sodium current in an in-vitro HEK293T cell system while also demonstrating a possible dominant negative outcome in the same study (Yang_2017). The following publications have been ascertained in the context of this evaluation (PMID: 30059973, 34219138, 28600387, 29759671, 28341781, 28159958). ClinVar contains an entry for this variant (Variation ID: 201570). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs794728922; hg19: chr3-38601740;